1. Field of the Invention
The present invention relates to novel compounds having retinoid and/or retinoid antagonist-like biological activity. More specifically, the present invention relates to alkyl or aryl substituted dihydronaphthalene derivatives which bind to retinoid receptors and have retinoid-like or retinoid antagonist-like biological activity.
2. Background Art
Compounds which have retinoid-like activity are well known in the art, and are described in numerous United States and other patents and in scientific publications. It is generally known and accepted in the art that retinoid-like activity is useful for treating animals of the mammalian species, including humans, for curing or alleviating the symptoms and conditions of numerous diseases and conditions. In other words, it is generally accepted in the art that pharmaceutical compositions having a retinoid-like compound or compounds as the active ingredient are useful as regulators of cell proliferation and differentiation, and particularly as agents for treating skin-related diseases, including, actinic keratoses, arsenic keratoses, inflammatory and non-inflammatory acne, psoriasis, ichthyoses and other keratinization and hyperproliferative disorders of the skin, eczema, atopic dermatitis, Darriers disease, lichen planus, prevention and reversal of glucocorticoid damage (steroid atrophy), as a topical anti-microbial, as skin anti-pigmentation agents and to treat and reverse the effects of age and photo damage to the skin. Retinoid compounds are also useful for the prevention and treatment of cancerous and precancerous conditions, including, premalignant and malignant hyperproliferative diseases such as cancers of the breast, skin, prostate, cervix, uterus, colon, bladder, esophagus, stomach, lung, larynx, oral cavity, blood and lymphatic system, metaplasias, dysplasias, neoplasias, leukoplakias and papillomas of the mucous membranes and in the treatment of Kaposi""s sarcoma. In addition, retinoid compounds can be used as agents to treat diseases of the eye, including, without limitation, proliferative vitreoretinopathy (PVR), retinal detachment, dry eye and other corneopathies, as well as in the treatment and prevention of various cardiovascular diseases, including, without limitation, diseases associated with lipid metabolism such as dyslipidemias, prevention of post-angioplasty restenosis and as an agent to increase the level of circulating tissue plasminogen activator (TPA). Other uses for retinoid compounds include the prevention and treatment of conditions and diseases associated with human papilloma virus (HPV), including warts and genital warts, various inflammatory diseases such as pulmonary fibrosis, ileitis, colitis and Krohn""s disease, neurodegenerative diseases such as Alzheimer""s disease, Parkinson""s disease and stroke, improper pituitary function, including insufficient production of growth hormone, modulation of apoptosis, including both the induction of apoptosis and inhibition of T-Cell activated apoptosis, restoration of hair growth, including combination therapies with the present compounds and other agents such as MinoxidilR, diseases associated with the immune system, including use of the present compounds as immunosuppressants and immunostimulants, modulation of organ transplant rejection and facilitation of wound healing, including modulation of chelosis.
U.S. Pat. No. 4,740,519 (Shroot et al.), U.S. Pat. No. 4,826,969 (Maignan et al.), U.S. Pat. No. 4,326,055 (Loeliger et al.), U.S. Pat. No. 5,130,335 (Chandraratna et al.), U.S. Pat. No. 5,037,825 (Klaus et al.), U.S. Pat. No. 5,231,113 (Chandraratna et), U.S. Pat. No. 5,324,840 (Chandraratna), U.S. Pat. No. 5,344,959 (Chandraratna), U.S. Pat. No. 5,130,335 (Chandraratna et al.), Published European Patent Application Nos. 0 176 034 A (Wuest et al.), 0 350 846 A (Klaus et al.), 0 176 032 A (Frickel et al.), 0 176 033 A (Frickel et al.), 0 253 302 A (Klaus et at), 0 303 915 A (Bryce et al.), UK Patent Application GB 2190378 A (Klaus et al.), German Patent Application Nos. DE 3715955 A1 (Klaus et al.), DE 3602473 A1 (Wuest et al. and the articles J. Amer. Acad. Derm. 15: 756-764 (1986) (Sporn et al.), Chem. Pharm. Bull. 33: 404-407 (1985) (Shudo et al.), J. Med Chem. 1988 31, 2182-2192 (Kagechika et al.), Chemistry and Biology of Synthetic Retinoids CRC Press Inc. 1990 p 334-335, 354 (Dawson et al.), describe or relate to compounds which include a tetrahydronaphthyl moiety and have retinoid-like or related biological activity. U.S. Pat. No. 4,391,731 (Boller et al.) describes tetrahydronaphthalene derivatives which are useful in liquid crystal compositions.
Published European Patent application Nos. 0 661 259 A1 and 0 661 261 A1 (Bristol-Myers Squibb) describe further dihydronaphthalene and naphthalene derivatives which are said in the disclosures to have retinoid-like biological activity.
U.S. Pat. Nos. 4,980,369, 5,006,550, 5,015,658, 5,045,551, 5,089,509, 5,134,159; 5,162,546, 5,234,926, 5,248,777, 5,264,578, 5,272,156, 5,278,318, 5,324,744, 5,346,895, 5,346,915, 5,348,972, 5,348,975, 5,380,877, 5,399,561, 5,407,937, (assigned to the same assignee as the present application) and patents and publications cited therein, describe or relate to chroman, thiochroman and 1,2,3,4-tetrahydroquinoline derivatives which have retinoid-like biological activity. Still further, several co-pending applications and recently issued patents which are assigned to the assignee of the present application, are directed to further compounds having retinoid-like activity.
Although pharmaceutical compositions containing retinoids have well established utility (as is demonstrated by the foregoing citation of patents and publications from the voluminous literature devoted to this subject) retinoids also cause a number of undesired side effects at therapeutic dose levels, including headache, teratogenesis, mucocutaneous toxicity, musculoskeletal toxicity, dyslipidemias, skin irritation, headache and hepatotoxicity. These side effects limit the acceptability and utility of retinoids for treating disease.
It is now general knowledge in the art that two main types of retinoid receptors exist in mammals (and other organisms). The two main types or families of receptors respectively designated the RARs and RXRs. Within each type there are subtypes; in the RAR family the subtypes are designated RARxcex1, RARxcex2 and RARxcex3, in RXR the subtypes are: RXRxcex1, RXBxcex2 and RXRxcex3. It has also been established in the art that the distribution of the two main retinoid receptor types, and of the several sub-types is not uniform in the various tissues and organs of mammalian organisms. Moreover, it is generally accepted in the art that many unwanted side effects of retinoids are mediated by one or more of the RAR receptor subtypes. Accordingly, among compounds having agonist-like activity at retinoid receptors, specificity or selectivity for one of the main types or families, and even specificity or selectivity for one or more subtypes within a family of receptors, is considered a desirable pharmacological property. Some compounds bind to one or more RAR receptor subtypes, but do not trigger the response which is triggered by agonists of the same receptors. A compound that binds to a biological receptor but does not trigger an agonist-like response is usually termed an antagonist. Accordingly, the xe2x80x9ceffectxe2x80x9d of compounds on retinoid receptors may fall in the range of having no effect at all, (inactive compound, neither agonist nor antagonist), the compound may elicit an agonist-like response on all receptor subtypes (pan-agonist), or a compound may be a partial agonist and/or partial antagonist of certain receptor subtypes if the compound binds to but does not activate certain receptor subtype or subtypes but elicits an agonist-like response in other receptor subtype or subtypes. A pan antagonist is a compound that binds to all known retinoid receptors but does not elicit an agonist-like response in any of the receptors.
It has been recently discovered and described in a pending application assigned to the same assignee as the present application that retinoid antagonist-like activity of a compound is also a useful property, in that such antagonist compounds can be utilized to block certain undesired side effects of retinoids, to serve as antidotes to retinoid overdose or poisoning, and may lend themselves to other pharmaceutical applications as well. More particularly, regarding the published scientific and patent literature in this field, published PCT application WO 94/14777 describes certain heterocyclic carboxylic acid derivatives which bind to RAR retinoid receptors and are said in the application to be useful for treatment of certain diseases or conditions, such as acne, psoriasis, rheumatoid arthritis and viral infections. A similar disclosure is made in the article by Yoshimura et al. J Med. Chem. 1995, 38, 3163-3173. Kaneko et al. Med. Chem Res. (1991) 1:220-225; Apfel et al. Proc. Natl. Acad. Sc. USA Vol 89 pp 7129-7133 Augusty 1992 Cell Biology; Eckhardt et al. Toxicology Letters, 70 (1994) 299-308; Keidel et al. Molecular and Cellular Biology, Vol 14, No. 1, January 1994, p 287-298; and Eyrolles et al. J. Med. Chem. 1994, 37, 1508-1517 describe compounds which have antagonist like activity at one or more of the RAR retinoid subtypes.
Among the compounds of Formulas 1 through 6, the present invention covers the compounds of Formula 6. Compounds of the remaining formulas are disclosed here inasmuch as the methods of their synthesis pertains to the best modes of the presently contemplated synthetic routes leading to the compounds of Formula 6. Thus the present invention pertains to compounds of Formula 6. 
wherein X1 is [C(R1)2]n where R1 is independently H or alkyl of 1 to 6 carbons, and n is an integer between 0 and 2;
X2 is S or O;
Z is xe2x80x94Nxe2x95x90Nxe2x80x94,
xe2x80x94N(O)xe2x95x90Nxe2x80x94,
xe2x80x94Nxe2x95x90N(O)xe2x80x94,
xe2x80x94Nxe2x95x90CR1xe2x80x94,
xe2x80x94CR1xe2x95x90N,
xe2x80x94(CR1xe2x95x90CR1)nxe2x80x2xe2x80x94 where nxe2x80x2 is an integer having the value 0-5,
xe2x80x94COxe2x80x94NR1xe2x80x94,
xe2x80x94CSxe2x80x94NR1xe2x80x94,
xe2x80x94NR1xe2x80x94CO,
xe2x80x94NR1xe2x80x94CS,
xe2x80x94COOxe2x80x94,
xe2x80x94OCOxe2x80x94;
xe2x80x94CSOxe2x80x94;
xe2x80x94OCSxe2x80x94;
xe2x80x94COxe2x80x94CR1xe2x95x90CR1xe2x80x94;
R2 is hydrogen, lower alkyl of 1 to 6 carbons, F, Cl, Br, I, CF3, fluoro substituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons, or alkylthio of 1 to 6 carbons;
R3 is hydrogen, lower alkyl of 1 to 6 carbons or F;
m is an integer having the value of 0-3;
o is an integer having the value of 0-4;
R4 is hydrogen, alkyl of 1 to 10 carbons, alkenyl of 2 to 10 carbons and having 1 to 3 double bonds, alkynyl having 2 to 10 carbons and 1 to 3 triple bonds, carbocyclic aryl selected from the group consisting of phenyl, C1-C10-alkylphenyl, naphthyl, C1-C10-alkyl-naphthyl, phenyl-C1-C10alkyl, napthyl-C1-C10alkyl; CN, or (CH2)pCO2R8 where p is an integer between 0 to 10;
R5 is hydrogen, alkyl of 1 to 10 carbons, fluoro-substituted alkyl of 1 to 10 carbons, alkenyl of 2 to 10 carbons and having 1 to 3 double bonds, alkynyl having 2 to 10 carbons and 1 to 3 triple bonds, carbocyclic aryl selected from the group consisting of phenyl, C1-C10-alkylphenyl, naphthyl, C1-C10-alkylnaphthyl, phenyl-C1-C10alkyl, napthyl-C1-C10alkyl; Si(C1-6alkyl)3, COR14, camphanoyl, C(R15)(R16)X2R17;
Y is a phenyl or naphthyl group, or heteroaryl selected from a group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyl and heteroaryl groups being optionally substituted with one or two R2 groups, or
when Z is xe2x80x94(CR1xe2x95x90CR1)nxe2x80x2xe2x80x94 and nxe2x80x2 is 3, 4 or 5 then Y represents a direct valence bond between said (CR2xe2x95x90CR2)nxe2x80x2 group and B;
A is (CH2)q where q is 0-5, lower branched chain alkyl having 3-6 carbons, cycloalkyl having 3-6 carbons, alkenyl having 2-6 carbons and 1 or 2 double bonds, alkynyl having 2-6 carbons and 1 or 2 triple bonds;
B is hydrogen, COOH or a pharmaceutically acceptable salt thereof, COOR8, CONR9R10, xe2x80x94CH2OH, CH2OR11, CH2OCOR11, CHO, CH(OR12)2, CHOR13O, xe2x80x94COR7, CR7(OR12)2, CR7OR13O, or Si(C1-6alkyl) 3, where R7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons, R8 is an alkyl group of 1 to 10 carbons or (trimethylsilyl)alkyl where the alkyl group has 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or R8 is phenyl or lower alkylphenyl, R9 and R10 independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyl or lower alkylphenyl, R11 is lower alkyl, phenyl or lower alkylphenyl, R12 is lower alkyl, and R13 is divalent alkyl radical of 2-5 carbons;
R14 is hydrogen, alkyl of 1 to 10 carbons, alkenyl of 2 to 10 carbons and having 1 to 3 double bonds, alkynyl having 2 to 10 carbons and 1 to 3 triple bonds, carbocyclic aryl selected from the group consisting of phenyl, C1-C10-alkylphenyl, naphthyl, C1-C10-alkylnaphthyl, phenyl-C1-C10alkyl, napthyl-C1-C10alkyl, and
R15 and R16 are hydrogen or lower alkyl of 1 to 6 carbons, R17 is lower alkyl of 1 to 6 carbons, or R16 and R17 jointly form a ring having a total of 4 to 5 carbons and the X2 heteroatom;
compounds of Formula 2
wherein X1 is [C(R1)2]n where R1 is independently H or alkyl of 1 to 6 carbons, and n is an integer between 0 and 2;
X2 is S or O;
Z is xe2x80x94Nxe2x95x90Nxe2x80x94,
xe2x80x94N(O)xe2x95x90Nxe2x80x94,
xe2x80x94Nxe2x95x90N(O)xe2x80x94,
xe2x80x94Nxe2x95x90CR1xe2x80x94,
xe2x80x94CR1xe2x95x90N,
xe2x80x94(CR1xe2x95x90CR1)nxe2x80x2xe2x80x94 where nxe2x80x2 is an integer having the value 0-5,
xe2x80x94COxe2x80x94NR1xe2x80x94,
xe2x80x94CSxe2x80x94NR1xe2x80x94,
xe2x80x94NR1xe2x80x94CO,
xe2x80x94NR1xe2x80x94CS,
xe2x80x94COOxe2x80x94,
xe2x80x94OCOxe2x80x94;
xe2x80x94CSOxe2x80x94;
xe2x80x94OCSxe2x80x94;
xe2x80x94COxe2x80x94CR1xe2x95x90CR1xe2x80x94;
R2 is hydrogen, lower alkyl of 1 to 6 carbons, F, Cl, Br, I, CF3, fluoro substituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons, or alkylthio of 1 to 6 carbons;
R3 is hydrogen, lower alkyl of 1 to 6 carbons or F;
m is an integer having the value of 0-3;
o is an integer having the value of 0-4;
Y is a phenyl or naphthyl group, or heteroaryl selected from a group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyl and heteroaryl groups being optionally substituted with one or two R2groups, or
when Z is xe2x80x94(CR1xe2x95x90CR1)nxe2x80x2xe2x80x94 and nxe2x80x2 is 3, 4 or 5 then Y represents a direct valence bond between said (CR2xe2x95x90CR2)nxe2x80x2 group and B;
A is (CH2)q where q is 0-5, lower branched chain alkyl having 3-6 carbons, cycloalkyl having 3-6 carbons, alkenyl having 2-6 carbons and 1 or 2 double bonds, alkynyl having 2-6 carbons and 1 or 2 triple bonds;
B is hydrogen, COOH or a pharmaceutically acceptable salt thereof, COOR8, CONR9R10, xe2x80x94CH2OH, CH2OR11, CH2OCOR11, CHO, CH(OR12)2, CHOR13O, xe2x80x94COR7, CR7(OR12)2, CR7OR13O, or Si(C1-6alkyl) 3, where R7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons, R8 is an alkyl group of 1 to 10 carbons or (trimethylsilyl)alkyl where the alkyl group has 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or R8 is phenyl or lower alkylphenyl, R9 and R10 independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyl or lower alkylphenyl, R11 is lower alkyl, phenyl or lower alkylphenyl, R12 is lower alkyl, and R13 is divalent alkyl radical of 2-5 carbons, and
R18 is alkyl of 1 to 10 carbons, fluoro-substituted ally of 1 to 10 carbons, or the two R18 groups jointly form a ring having a total of 3 to 6 carbons, or the two X2R18 groups jointly symbolize an oxo (xe2x95x90O) or a thio (xe2x95x90S) function, or each of the two X2R18 groups is H;
compounds of Formula 3
wherein X1 is [C(R1)2]n where R1 is independently H or alkyl of 1 to 6 carbons, and n is an integer between 0 and 2;
Z is xe2x80x94Nxe2x95x90Nxe2x80x94,
xe2x80x94N(O)xe2x95x90Nxe2x80x94,
xe2x80x94Nxe2x95x90N(O)xe2x80x94,
xe2x80x94Nxe2x95x90CR1xe2x80x94,
xe2x80x94CR1xe2x95x90N,
xe2x80x94(CR1xe2x95x90CR1)nxe2x80x2xe2x80x94 where nxe2x80x2 is an integer having the value 0-5,
xe2x80x94COxe2x80x94NR1xe2x80x94,
xe2x80x94CSxe2x80x94NR1xe2x80x94,
xe2x80x94NR1xe2x80x94CO,
xe2x80x94NR1xe2x80x94CS,
xe2x80x94COOxe2x80x94,
xe2x80x94OCOxe2x80x94;
xe2x80x94CSOxe2x80x94;
xe2x80x94OCSxe2x80x94;
xe2x80x94COxe2x80x94CR1xe2x95x90CR1xe2x80x94;
R2 is hydrogen, lower alkyl of 1 to 6 carbons, F, Cl, Br, I, CF3, fluoro substituted alkyl of 1 to 6 carbons, OH SH alkoxy of 1 to 6 carbons, or alkylthio of 1 to 6 carbons;
R3 is hydrogen, lower alkyl of 1 to 6 carbons or F;
m is an integer having the value of 0-3;
o is an integer having the value of 0-4;
Y is a phenyl or naphthyl group, or heteroaryl selected from a group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyl and heteroaryl groups being optionally substituted with one or two R2 groups, or
when Z is xe2x80x94(CR1xe2x95x90CR1)nxe2x80x2xe2x80x94 and nxe2x80x2 is 3, 4 or 5 then Y represents a direct valence bond between said (CR2xe2x95x90CR2)nxe2x80x2 group and B;
A is (CH2)q where q is 0-5, lower branched chain alkyl having 3-6 carbons, cycloalkyl having 3-6 carbons, alkenyl having 2-6 carbons and 1 or 2 double bonds, alkynyl having 2-6 carbons and 1 or 2 triple bonds;
B is hydrogen, COOH or a pharmaceutically acceptable salt thereof, COOR8, CONR9R10, xe2x80x94CH2OH, CH2OR11, CH2OCOR11, CHO, CH(OR12)2, CHOR13O, xe2x80x94COR7, CR7(OR12)2, CR7OR13O, or Si(C1-6alkyl) 3, where R7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons, R8 is an alkyl group of 1 to 10 carbons or (trimethylsilyl)alkyl where the alkyl group has 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or R8 is phenyl or lower alkylphenyl, R9 and R10 independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons; or phenyl or lower alkylphenyl, R11 is lower alkyl, phenyl or lower alkylphenyl, R12 is lower alkyl, and R13 is divalent alkyl radical of 2-5 carbons, and
R19 is independently hydrogen, alkyl of 1 to 10 carbons, fluoro-substituted alkyl of 1 to 10 carbons, alkenyl of 2 to 10 carbons and having 1 to 3 double bonds, alkynyl having 2 to 10 carbons and 1 to 3 triple bonds, carbocyclic aryl selected from the group consisting of phenyl, C1-C10-alkylphenyl, naphthyl, C1-C10-alkylnaphthyl, phenyl-C1-C10alkyl, naphthyl-C1-C10alkyl; heteroaryl selected from the group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyl and heteroaryl groups being optionally substituted with one or two R2 groups, further R19 is independently CN, CHO, CH(OR12)2, CHOR13O, (CH2)pCO2R8, (CH2)pCH2OH, (CH2)pCH2OR11, (CH2)pCH2OCOR11, where p is an integer between 0 to 10, or the two R19 groups jointly represent 3 to 8 methylene groups which together with the alkylidene carbon complete a ring, the ring optionally containing 1 to 2 double bonds and the ring being optionally substituted with 1 or 2 R2 groups;
compounds of Formula 4
wherein X1 is [C(R1)2]n where R1 is independently H or alkyl of 1 is to 6 carbons, and n is an integer between 0 and 2;
Z is xe2x80x94Nxe2x95x90Nxe2x80x94,
xe2x80x94N(O)xe2x95x90Nxe2x80x94,
xe2x80x94Nxe2x95x90N(O)xe2x80x94,
xe2x80x94Nxe2x95x90CR1xe2x80x94,
xe2x80x94CR1xe2x95x90N,
xe2x80x94(CR1xe2x95x90CR1)nxe2x80x2xe2x80x94 where nxe2x80x2 is an integer having the value 0-5,
xe2x80x94COxe2x80x94NR1xe2x80x94,
xe2x80x94CSxe2x80x94NR1xe2x80x94,
xe2x80x94NR1xe2x80x94CO,
xe2x80x94NR1xe2x80x94CS,
xe2x80x94COOxe2x80x94,
xe2x80x94OCOxe2x80x94;
xe2x80x94CSOxe2x80x94;
xe2x80x94OCSxe2x80x94;
xe2x80x94COxe2x80x94CR1xe2x95x90CR1xe2x80x94;
R2 is hydrogen, lower alkyl of 1 to 6 carbons, F, Cl, Br, I, CF3, fluoro substituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons, or alkylthio of 1 to 6 carbons;
R3 is hydrogen, lower alkyl of 1 to 6 carbons or F;
m is an integer having the value of 0-3;
o is an integer having the value of 0-4;
Y is a phenyl or naphthyl group, or heteroaryl selected from a group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyl and heteroaryl groups being optionally substituted with one or two R2 groups, or
when Z is xe2x80x94(CR1xe2x95x90CR1)nxe2x80x2xe2x80x94 and nxe2x80x2 is 3, 4 or 5 then Y represents a direct valence bond between said (CR2xe2x95x90CR2)nxe2x80x2 group and B;
A is (CH2)q where q is 0-5, lower branched chain alkyl having 3-6 carbons, cycloalkyl having 3-6 carbons, alkenyl having 2-6 carbons and 1 or 2 double bonds, alkynyl having 2-6 carbons and 1 or 2 triple bonds;
B is hydrogen, COOH or a pharmaceutically acceptable salt thereof, COOR8, CONR9R10, xe2x80x94CH2OH, CH2OR11, CH2OCOR11, CHO, CH(OR12)2, CHOR13O, xe2x80x94COR7, CR7(OR12)2, CR7OR13O, or Si(C1-6alkyl) 3, where R7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons, R8 is an alkyl group of 1 to 10 carbons or (trimethylsilyl)alkyl where the alkyl group has 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or R8 is phenyl or lower alkylphenyl, R9 and R10 independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyl or lower alkylphenyl, R11 is lower alkyl, phenyl or lower alkylphenyl, R12 is lower alkyl, and R13 is divalent alkyl radical of 2-5 carbons, and
Z2 is OR1 or OR18 where R18 is is phenyl, benzyl, lower alkyl or lower alkoxy substituted phenyl, or Z2 is OSi(R2)3, OCOR14, OC(R15)(R16)X2R17, N(R14)2, NHCON(R14)2, NHCSN(R14)2, where X2 is O or S; R14 is hydrogen, alkyl of 1 to 10 carbons, alkenyl of 2 to 10 carbons and having 1 to 3 double bonds, alkynyl having 2 to 10 carbons and 1 to 3 triple bonds, carbocyclic aryl selected from the group consisting of phenyl, C1-C10-alkylphenyl, naphthyl, C1-C10-alkylnaphthyl, phenyl-C1-C10-alkyl naphthyl-C1-C10alkyl; R15 and R16 are hydrogen or lower alkyl of 1 to 6 carbons, R17 is lower alkyl of 1 to 6 carbons, or R16 and R17 jointly form a ring having a total of 4 to 5 carbons and the X2 heteroatom;
compounds of Formula 5
wherein X1 is [C(R1)2]n where R1 is independently H or alkyl of 1 to 6 carbons, and n is an integer between 0 and 2;
Z is xe2x80x94Nxe2x95x90Nxe2x80x94,
xe2x80x94N(Oxe2x95x90Nxe2x80x94,
xe2x80x94Nxe2x95x90N(O)xe2x80x94,
xe2x80x94Nxe2x95x90CR1xe2x80x94,
xe2x80x94CR1xe2x95x90N,
xe2x80x94(CR1xe2x95x90CR1)nxe2x80x2xe2x80x94 where nxe2x80x2 is an integer having the value 0-5,
xe2x80x94COxe2x80x94NR1xe2x80x94,
xe2x80x94CSxe2x80x94NR1xe2x80x94,
xe2x80x94NR1xe2x80x94CO,
xe2x80x94NR1xe2x80x94CS,
xe2x80x94COOxe2x80x94,
xe2x80x94OCOxe2x80x94;
xe2x80x94CSOxe2x80x94;
xe2x80x94OCSxe2x80x94;
xe2x80x94COxe2x80x94CR1xe2x95x90CR1xe2x80x94;
R2 is hydrogen, lower alkyl of 1 to 6 carbons, F, Cl, Br, I, CF3, fluoro substituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons, or alkylthio of 1 to 6 carbons;
R3 is hydrogen, lower alkyl of 1 to 6 carbons or F;
m is an integer having the value of 0-3;
o is an integer having the value of 0-3;
Y is a phenyl or naphthyl group, or heteroaryl selected from a group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyl and heteroaryl groups being optionally substituted with one or two R2 groups, or
when Z is xe2x80x94(CR1xe2x95x90CR1)nxe2x80x2xe2x80x94 and nxe2x80x2 is 3, 4 or 5 then Y represents a direct valence bond between said (CR2xe2x95x90CR2)nxe2x80x2 group and B;
A is (CH2)q where q is 0-5, lower branched chain alkyl having 3-6 carbons, cycloalkyl having 3-6 carbons, alkenyl having 2-6 carbons and 1 or 2 double bonds, alkynyl having 2-6 carbons and 1 or 2 triple bonds;
B is hydrogen, COOH or a pharmaceutically acceptable salt thereof, COOR8, CONR9R10, xe2x80x94CH2OH, CH2OR11, CH2OCOR11, CHO, CH(OR12)2, CHOR13O, xe2x80x94COR7, CR7(OR12)2, CR7OR13O, or Si(C1-6alkyl)3, where R7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons, R8 is an alkyl group of 1 to 10 carbons or (trimethylsilyl)alkyl where the alkyl group has 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or R8 is phenyl or lower alkylphenyl, R9 and R10 independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyl or lower alkylphenyl, R11 is lower alkyl, phenyl or lower alkylphenyl, R12 is lower alkyl, and R13 is divalent alkyl radical of 2-5 carbons;
X2 is O, S, SO or SO2, and
R20 is Si(C1-6alkyl)3, R14 COR14, SO2R21, where R14 is hydrogen, alkyl of 1 to 10 carbons, alkenyl of 2 to 10 carbons and having 1 to 3 double bond, alkynyl having 2 to 10 carbons and 1 to 3 triple bonds; carbocyclic aryl selected from the group consisting of phenyl, C1-C10-alkylphenyl, naphthyl, C1-C10-alkylnaphthyl, phenyl-C1-C10alkyl, napthyl-C1-C10alkyl, or R20 is hydroxyalkyl, aminoalkyl or thioalkyl having 1 to 10 carbons; and R21 is alkyl of 1 to 10 carbons, fluoroalkyl of 1 to 10 carbons, or carbocyclic aryl selected from the group consisting of phenyl, C1-C10-alkylphenyl and phenyl-C1-C10alkyl, and
compounds of Formula 6
wherein X1 is [C(R1)2]n where R1 is independently H or alkyl of 1 to 6 carbons, and n is an integer between 0 and 2;
Z is xe2x80x94Nxe2x95x90Nxe2x80x94,
xe2x80x94N(O)xe2x95x90Nxe2x80x94,
xe2x80x94Nxe2x95x90N(O)xe2x80x94,
xe2x80x94Nxe2x95x90CR1xe2x80x94,
xe2x80x94CR1xe2x95x90N,
xe2x80x94(CR1xe2x95x90CR1)nxe2x80x2xe2x80x94 where nxe2x80x2 is an integer having the value 0-5,
xe2x80x94COxe2x80x94NR1xe2x80x94,
xe2x80x94CSxe2x80x94NR1xe2x80x94,
xe2x80x94NR1xe2x80x94CO,
xe2x80x94NR1xe2x80x94CS,
xe2x80x94COOxe2x80x94,
xe2x80x94OCOxe2x80x94;
xe2x80x94CSOxe2x80x94;
xe2x80x94OCSxe2x80x94;
xe2x80x94COxe2x80x94CR1xe2x95x90CR1xe2x80x94;
R2 is hydrogen, lower alkyl of 1 to 6 carbons, F, Cl, Br, I, CF3, fluoro substituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons, or alkylthio of 1 to 6 carbons;
R3 is hydrogen, lower alkyl of 1 to 6 carbons or F;
m is an integer having the value of 0-3;
o is an integer having the value of 0-3;
Y is a phenyl or naphthyl group, or heteroaryl selected from a group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyl and heteroaryl groups being optionally substituted with one or two R2 groups, or
when Z is xe2x80x94(CR1xe2x95x90CR1)nxe2x80x2xe2x80x94 and nxe2x80x2 is 3, 4 or 5 then Y represents a direct valence bond between said (CR2xe2x95x90CR2)nxe2x80x2 group and B;
A is (CH2)q where q is 0-5, lower branched chain alkyl having 3-6 carbons, cycloalkyl having 3-6 carbons, alkenyl having 2-6 carbons and 1 or 2 double bonds, alkynyl having 2-6 carbons and 1 or 2 triple bonds;
B is hydrogen, COOH or a pharmaceutically acceptable salt thereof, COOR8, CONR9R10, xe2x80x94CH2OH CH2OR11, CH2OCOR11, CHO, CH(OR12)2, CHOR13O, xe2x80x94COR7, CR7(OR12)2, CR7OR13O, or Si(C1-6alkyl)3, where R7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons, R8 is an alkyl group of 1 to 10 carbons or (trimethylsilyl)alkyl where the alkyl group has 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or R8 is phenyl or lower alkylphenyl, R9 and R10 independently are hydrogen, an alkyl group of 1 to 10 carbons; or a cycloalkyl group of 5-10 carbons, or phenyl or lower alkylphenyl, R11 is lower alkyl phenyl or lower alkylphenyl, R12 is lower alkyl, and R13 is divalent alkyl radical of 2-5 carbons; and
R14 is (R15)r-substituted alkyl of 1-6 carbons, (R15)r-substituted alkenyl of 1-6 carbons and 1 or 2 double bonds, (R15)r-substituted alkynyl of 1-6 carbons and 1 or 2 triple bonds, (R15)r-phenyl, (R15)r-naphthyl, or (R15)r-heteroaryl where the heteroaryl group has 1 to 3 heteroatoms selected from the group consisting of O, S and N, r is an integer having the values of 0-5, and
R15 is independently H, F, Cl, Br, I, NO2, N(R8)2, N(R8)COR8, NR8CON(R8)2, OH, OCOR8, OR8, CN, COOH, COOR8 an alkyl group having 1 to 10 carbons, fluoro substituted alkyl group having 1 to 10 carbons, an alkenyl group having 1 to 10 carbons and 1 to 3 double bonds, alkynyl group having 1 to 10 carbons and 1 to 3 triple bonds, or a (trialkyl)silyl or (trialkyl)silyloxy group where the alkyl groups independently have 1 to 6 carbons.
In a second aspect, this invention relates to the use of the compounds of Formula 1 through Formula 6 for the treatment of skin-related diseases, including, without limitation, actinic keratoses, arsenic keratoses, inflammatory and non-inflammatory acne, psoriasis, ichthyoses and other keratinization and hyperproliferative disorders of the skin, eczema, atopic dermatitis, Darriers disease, lichen planus, prevention and reversal of glucocorticoid damage (steroid atrophy), as a topical anti-microbial, as skin anti-pigmentation agents and to treat and reverse the effects of age and photo damage to the skin. The compounds are also useful for the prevention and treatment of cancerous and precancerous conditions, including, premalignant and malignant hyperproliferative diseases such as cancers of the breast, skin, prostate, cervix, uterus, colon, bladder, esophagus, stomach, lung, larynx, oral cavity, blood and lymphatic system, metaplasias, dysplasias, neoplasias, leukoplakias and papillomas of the mucous membranes and in the treatment of Kaposi""s sarcoma. In addition, the present compounds can be used as agents to treat diseases of the eye, including, without limitation, proliferative vitreoretinopathy (PVR), retinal detachment, dry eye and other corneopathies, as well as in the treatment and prevention of various cardiovascular diseases, including, without limitation, diseases associated with lipid metabolism such as dyslipidemias, prevention of post-angioplasty restenosis and as an agent to increase the level of circulating tissue plasminogen activator (TPA). Other uses for the compounds of the present invention include the prevention and treatment of conditions and diseases associated with Human papilloma virus (HPV), including warts and genital warts, various inflammatory diseases such as pulmonary fibrosis, ileitis, colitis and Krohn""s disease, neurodegenerative diseases such as Alzheimer""s disease, Parkinson""s disease and stroke, improper pituitary function, including insufficient production of growth hormone, modulation of apoptosis, including both the induction of apoptosis and inhibition of T-Cell activated apoptosis, restoration of hair growth, including combination therapies with the present compounds and other agents such as MinoxidilR, diseases associated with the immune system, including use of the present compounds as immunosuppressants and immunostimulants, modulation of organ transplant rejection and facilitation of wound healing, including modulation of chelosis.
Alternatively, those compounds of the invention which act as antagonists of one or more retinoid receptor subtypes are useful to prevent certain undesired side effects of retinoids which are administered for the treatment or prevention of certain diseases or conditions. For this purpose the retinoid antagonist compounds of the invention may be co-administered with retinoids. The compounds of the present invention are also useful in the treatment of acute or chronic toxicity resulting from overdose or poisoning by retinoid drugs or Vitamin A.
This invention also relates to a pharmaceutical formulation comprising a compound of Formula 1 through Formula 6 in admixture with a pharmaceutically acceptable excipient, said formulation being adapted for administration to a mammal, including a human being, to treat or alleviate the conditions which were described above as treatable by retinoids, to be co-administered with retinoids to eliminate or reduce side effects of retinoids, or to treat retinoid or Vitamin A overdose or poisoning.
Assay of Retinoid-Like or Retinoid Antagonist-Like Biological Activity
A classic measure of retinoic acid activity involves measuring the effects of retinoic acid on ornithine decarboxylase. The original work on the correlation between retinoic acid and decrease in cell proliferation was done by Verma and Boutwell, Cancer Research, 1977, 37,2196-2201. That reference discloses that ornithine decarboxylase (ODC) activity increased precedent to polyamine biosynthesis. It has been established elsewhere that increases in polyamine synthesis can be correlated or associated with cellular proliferation. Thus, if ODC activity could be inhibited, cell hyperproliferation could be modulated. Although all cases for ODC activity increases are unknown, it is known that 12-0-tetradecanoylphorbol-13-acetate (TPA) induces ODC activity. Retinoic acid inhibits this induction of ODC activity by TPA. An assay essentially following the procedure set out in Cancer Research: 1662-1670,1975 may be used to demonstrate inhibition of TPA induction of ODC by compounds of this invention. Activity of exemplary compounds of the present invention in the above-described ODC assay is disclosed in Table 1 which provides the IC60 concentration for the respective exemplary compound. (xe2x80x9cIC60xe2x80x9d is that concentration of the test compound which causes 60% inhibition in the ODC assay. By analogy, xe2x80x9cIC80, for example, is that concentration of the test compound which uses 80% inhibition in the ODC assay.)
Other assays described below, measure the ability of the compounds of the present invention to bind to, and/or activate various retinoid receptor subtypes. When in these assays a compound binds to a given receptor subtype and activates the transcription of a reporter gene through that subtype, then the compound is considered an agonist of that receptor subtype. Conversely, a compound is considered an antagonist of a given receptor subtype if in the below described co-tranfection assays the compound does not cause significant transcriptional activation of the receptor regulated reporter gene, but nevertheless binds to the receptor with a Kd value of less than proximately 1 micromolar. In the below described assays the ability of the compounds to bind to RARxcex1, RARxcex2, RARxcex3, RXRxcex1, RXRxcex2 and RXRr receptors, and the ability or inability of the compounds to activate transcription of a reporter gene through these receptor subtypes can be tested.
Specifically, a chimeric receptor transactivation assay which tests for agonist-like activity in the RARxcex1, RARxcex2, RARxcex3, RXRxcex1 receptor subtypes, and which is based on work published by Feigner P. L. and Holm M. (1989) Focus, 11 2 is described in detail in U.S. Pat. No. 5,455,265 the specification of which is hereby expressly incorporated by reference.
A holoreceptor transactivation assay and a ligand binding assay which measure the antagonist/agonist like activity of the compounds of the invention, or their ability to bind to the several retinoid receptor subtypes, respectively, are described in published. PCT Application No. WO WO93/11755 (particularly on pages 30-33 and 37-41) published on Jun. 24, 1993, the specification of which is also incorporated herein by reference. A description of the holoreceptor transactivation assay is also provided below.
Holoreceptor Transactivation Assay
CV1 cells (5,000 cells/well) were transfected with an RAR reporter plasmid MTV-TREp-LUC (50 ng) along with one of the RAR expression vectors (10 ng) in an automated 96-well format by the calcium phosphate procedure of Heyman et al. Cell 68, 397-406, 1992). For RXRxcex1 and RXRxcex3 transactivation assays, an RXR-responsive reporter plasmid CRBPII-tk-LUC (50 ng) along with the appropriate RXR expression vectors (10 ng) was used substantially as described by Heyman et al. above, and Allegretto et al. J. Biol. Chem. 268, 26625-26633. For RXRxcex2 transactivation assays, an RXR-responsive reporter plasmid CPRE-tk-LUC (50 mg) along with RXRxcex2 expression vector (10 mg) was used as described in above. These reporters contain DRI elements from human CRBPII and certain DRI elements from promoter, respectively. (see Mangelsdorf et al. The Retinoids: Biology, Chemistry and Medicine, pp 319-349, Raven Press Ltd., New York and Heyman et al. cited above) (1, 8). A xcex2-galactosidase (50 ng) expression vector was used as an internal control in the transfections to normalize for variations in transfection efficiency. The cells were transfected in triplicate for 6 hours, followed by incubation with retinoids for 36 hours, and the extracts were assayed for luciferase and xcex2-galactosidase activities. The detailed experimental procedure for holoreceptor transactivations has been described in Heyman et al. above, and Allegretto et al. cited above. The results obtained in this assay are expressed in EC50 numbers, as they are also in the chimeric receptor transactivation assay. The Heyman et al. Cell 68, 397-406, Allegretto et al. J. Biol. Chem. 268, 26625-26633, and Mangelsdorf et al. The Retinoids: Biology, Chemistry and Medicine, pp 319-349, Raven Press Ltd., New York, are expressly incorporated herein by reference. The results of ligand binding assay are expressed in Kd numbers. (See Cheng et al. Biochemical Pharmacology Vol. 22 pp 3099-3108, expressly incorporated herein by reference.)
Table 2 shows the results of the ligand binding assay for certain exemplary compounds of the invention for the receptor subtypes in the RAR group.
Modes of Administration
The compounds of this invention may be administered systemically or topically, depending on such considerations as the condition to be treated, need for site-specific treatment, quantity of drug to be administered, and numerous other considerations.
In the treatment of dermatoses, it will generally be preferred to administer the drug topically, though in certain cases such as treatment of severe cystic acne or psoriasis, oral administration may also be used. Any common topical formulation such as a solution, suspension, gel, ointment, or salve and the like may be used. Preparation of such topical formulations are well described in the art of pharmaceutical formulations as exemplified, for example, by Remington""s Pharmaceutical Science, Edition 17, Mack Publishing Company, Easton, Pa. For topical application, these compounds could also be administered as a powder or spray, particularly in aerosol form. If the drug is to be administered systemically, it may be confected as a powder, pill, tablet or the like or as a syrup or elixir suitable for oral administration. For intravenous or intraperitoneal administration, the compound will be prepared as a solution or suspension capable of being administered by injection. In certain cases, it may be useful to formulate these compounds by injection. In certain cases, it may be useful to formulate these compounds in suppository form or as extended release formulation for deposit under the skin or intramuscular injection.
Other medicaments can be added to such topical formulation for such secondary purposes as treating skin dryness; providing protection against light; other medications for treating dermatoses; medicaments for preventing infection, reducing irritation, inflammation and the like.
Treatment of dermatoses or any other indications known or discovered to be susceptible to treatment by retinoic acid-like compounds will be effected by administration of the therapeutically effective dose of one or more compounds of the instant invention. A therapeutic concentration will be that concentration which effects reduction of the particular condition, or retards it expansion. In certain instances, the compound potentially may be used in prophylactic manner to prevent onset of a particular condition.
A useful therapeutic or prophylactic concentration will vary from condition to condition and in certain instances may vary with the severity of the condition being treated and the patient""s susceptibility to treatment. Accordingly, no single concentration will be uniformly useful, but will require modification depending on the particularities of the disease being treated. Such concentrations can be arrived at through routine experimentation. However, it is anticipated that in the treatment of, for example, acne, or similar dermatoses, that a formulation containing between 0.01 and 1.0 milligrams per milliliter of formulation will constitute a therapeutically effective concentration for total application. If administered systemically, an amount between 0.01 and 5 mg per kg per day of body weight would be expected to effect a therapeutic result in the treatment of many diseases for which these compounds are useful.
Those partial or pan retinoid antagonist compounds of the invention, when used to take advantage of their antagonist property, can be co-administered to mammals, including humans, with retinoid agonists and, by means of pharmacological selectivity or site-specific delivery, preferentially prevent the undesired effects of certain retinoid agonists. The antagonist compounds of the invention can also be used to treat Vitamin A overdose, acute or chronic, resulting either from the excessive intake of vitamin A supplements or from the ingestion of liver of certain fish and animals that contain high levels of Vitamin A. Still further, the antagonist compounds of the invention can also be used to treat acute or chronic toxicity caused by retinoid drugs. It has been known in the art that the toxicities observed with hypervitaminosis A syndrome (headache, skin peeling, bone toxicity, dyslipidemias) are similar or identical with toxicities observed with other retinoids, suggesting a common biological cause, that is RAR activation. Because the antagonist compounds of the present invention block RAR activation, they are suitable for treating the foregoing toxicities.
Generally speaking, for therapeutic applications in mammals, the antagonist compounds of the invention can be admistered enterally or topically as an antidote to vitamin A, or antidote to retinoid toxicity resulting from overdose or prolonged exposure, after intake of the causative factor (vitamin A, vitamin A precursor, or other retinoid) has been discontinued. Alternatively, the antagonist compounds of the invention are co-administered with retinoid drugs, in situations where the retinoid provides a therapeutic benefit, and where the co-administered antagonist compound alleviates or eliminates one or more undesired side effects of the retinoid. For this type of application the antagonist compound may be administered in a site-specific manner, for example as a topically applied cream or lotion while the co-administered retinoid may be given enterally. For therapeutic applications the antagonist compounds of the invention, like the retinoid agonists compounds, are incorporated into pharmaceutical compositions, such as tablets, pills, capsules, solutions, suspensions, creams, ointments, gels, salves, lotions and the like, using such pharmaceutically acceptable excipients and vehicles which per se are well known in the art. For topical application, the antagonist compounds of the invention could also be administered as a powder or spray, particularly in aerosol form. If the drug is to be administered systemically, it may be confected as a powder, pill, tablet or the like or as a syrup or elixir suitable for oral administration. For intravenous or intraperitoneal administration, the compound will be prepared as a solution or suspension capable of being administered by injection. In certain cases, it may be useful to formulate these compounds by injection. In certain cases, it may be useful to formulate these compounds in suppository form or as extended release formulation for deposit under the skin or intramuscular injection.
The antagonist compounds also, like the retinoid agonists of the invention, will be administered in a therapeutically effective dose. A therapeutic concentration will be that concentration which effects reduction of the particular condition, or retards its expansion. When co-administering the compounds of the invention to block retinoid-induced toxicity or side effects, the antagonist compounds of the invention are used in a prophylactic manner to prevent onset of a particular condition, such as skin irritation.
A useful therapeutic or prophylactic concentration will vary from condition to condition and in certain instances may vary with the severity of the condition being treated and the patient""s susceptibility to treatment. Accordingly, no single concentration will be uniformly useful, but will require modification depending on the particularities of the chronic or acute retinoid toxicity or related condition being treated. Such concentrations can be arrived at through routine experimentation. However, it is anticipated that a formulation containing between 0.01 and 1.0 milligrams per mililiter of formulation will constitute a therapeutically effective concentration for total application. If administered systemically, an amount between 0.01 and 5 mg per kg per day of body weight would be expected to effect a therapeutic result.